IDE196 Combinations for Solid Tumors

Recruiting at9 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: IDEAYA Biosciences

Must not be taking: Statins, ALK inhibitors

Disqualifiers: Symptomatic brain metastases, AIDS, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2, multi-center, open-label basket study designed to evaluate the safety and anti-tumor activity of IDE196 in patients with solid tumors harboring GNAQ or GNA11 (GNAQ/11) mutations or PRKC fusions, including metastatic uveal melanoma (MUM), cutaneous melanoma, colorectal cancer, and other solid tumors. Phase 1 (dose escalation - monotherapy) will assess safety, tolerability and pharmacokinetics of IDE196 via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study. Phase 1 (dose escalation - binimetib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and binimetinib via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study. Phase 1 (dose escalation - crizotinib combination) will assess safety, tolerability and pharmacokinetics of IDE196 and crizotinib via standard dose escalation scheme and determine the recommended Phase 2 dose. Safety and anti-tumor activity will be assessed in the Phase 2 (dose expansion) part of the study. Evaluation of safety and efficacy across multiple doses may be explored in the dose optimization part of the study. Crizotinib monotherapy with crossover to combination cohort may be assessed for safety and to show the contribution of each study drug to anti-tumor activity. As of Protocol Amendment 10, Phase 1, Phase 2 dose expansion in IDE196 monotherapy, and Phase 2 dose expansion of IDE196 in combination with binimetinib have been fully enrolled. There were no patients enrolled in the crizotinib monotherapy cohorts.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that treatment with prohibited medications that cannot be discontinued prior to study entry is an exclusion criterion. It would be best to discuss your current medications with the trial team to determine if any need to be stopped.

What makes the drug IDE196 unique for treating solid tumors?

IDE196 (Darovasertib) is unique because it targets a specific protein involved in cancer cell growth, making it potentially effective for tumors with certain genetic mutations. This targeted approach is different from traditional chemotherapy, which affects all rapidly dividing cells. ^{1 2 3 4 5}

Research Team

George Cole Jr., MD

Principal Investigator

[e-mail]

Eligibility Criteria

This trial is for adults with certain solid tumors, including metastatic uveal melanoma, skin cancer, and colorectal cancer that have specific genetic mutations or fusions. Participants must have had prior treatment with a MEK inhibitor (except for Binimetinib Combination), measurable disease, good performance status (ECOG ≤1), life expectancy over 3 months, adequate organ function and cardiac function (for Binimetinib Combination), and agree to use contraception. Exclusions include symptomatic brain metastases, pregnancy/breastfeeding women, recent thromboembolic events or surgeries.

Inclusion Criteria

I am 18 years old or older.

I have a history of fainting.

My organs are working well.

Exclusion Criteria

I have previously been treated with a MEK inhibitor.

I have a muscle disorder that increases my CPK levels.

I have a history of fainting.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Dose Escalation

Assessment of safety, tolerability, and pharmacokinetics of IDE196, alone and in combination with binimetinib or crizotinib, to determine the recommended Phase 2 dose

28 days per cycle

Phase 2 Dose Expansion

Evaluation of safety and anti-tumor activity of IDE196, alone and in combination with binimetinib or crizotinib, at the recommended Phase 2 dose

Approx. 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approx. 48 months

Treatment Details

Interventions

• Binimetinib (Protein Kinase Inhibitor)
• Crizotinib (Protein Kinase Inhibitor)
• IDE196 (CAR T-cell Therapy)

Trial Overview The study tests the safety and effectiveness of IDE196 alone or in combination with Crizotinib or Binimetinib in patients whose tumors have GNAQ/11 mutations or PRKC fusions. It includes dose escalation to find the right amount of drug and then expands to more patients at this dose. The effects of food on IDE196's absorption are also studied.

Participant Groups

Group I: PK Substudy with Pravastatin (OBTP1B1 Substrate) Experimental Treatment 1 Intervention

A PK substudy with approximately 18 patients will be nested within the IDE196 and crizotinib combination expansion cohort to evaluate the impact on the pravastatin PK profile by the steady state exposures of IDE196.

Group II: Dose Optimization Crizotinib Combination Experimental Treatment 2 Interventions

IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Crizotinib dosed orally, twice daily (BID) for each 28-day cycle

Group III: Dose Expansion Monotherapy Experimental Treatment 1 Intervention

RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations or PRKC fusions (cutaneous melanoma, CRC, other solid tumors)

Group IV: Dose Expansion Crizotinib Combination Experimental Treatment 2 Interventions

RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations (cutaneous melanoma, CRC, other solid tumors) Previously treated MUM, Treatment naïve MUM, MUM patients with human leukocyte antigen (HLA)-A\*02:01 positive status

Group V: Dose Expansion Binimetinib Combination Experimental Treatment 2 Interventions

RP2D in MUM and non-MUM tumors harboring GNAQ/11 mutations (cutaneous melanoma, CRC, other solid tumors)

Group VI: Dose Escalation Monotherapy Experimental Treatment 1 Intervention

IDE196 dosed orally, twice daily (BID) for each 28-day cycle

Group VII: Dose Escalation Crizotinib Combination Experimental Treatment 2 Interventions

IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Crizotinib dosed orally, twice daily (BID) for each 28-day cycle

Group VIII: Dose Escalation Binimetinib Combination Experimental Treatment 2 Interventions

IDE196 dosed orally, twice daily (BID) for each 28-day cycle and Binimetinib dosed orally, twice daily (BID) for each 28-day cycle

Group IX: Crizotinib Monotherapy with Crossover to Combination Experimental Treatment 2 Interventions

Crizotinib dosed orally, twice daily (BID) for each 28-day cycle until disease progression then IDE196 added and dosed orally, twice daily (BID) for each 28-day cycle

Who Is Running the Clinical Trial?

IDEAYA Biosciences

Lead Sponsor

Trials

6

Recruited

1,300+

Findings from Research

In a phase 1 trial involving 30 pediatric patients with recurrent or refractory solid and CNS tumors, prexasertib was administered safely with no dose-limiting toxicities observed, establishing a recommended phase 2 dose of 150 mg/m2.

While the treatment did not result in objective responses, it did lead to stable disease in three patients, indicating some potential for disease control, particularly in specific tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515). Cash, T., Fox, E., Liu, X., et al.[2022]

In a study involving 20 children and young adults with recurrent/refractory cancers, the combination of the WEE1 inhibitor adavosertib and carboplatin showed significant hematologic toxicity, including prolonged neutropenia and thrombocytopenia, leading to dose adjustments.

Despite the toxicity, the treatment demonstrated some efficacy, with an overall response rate of 11%, particularly in patients with specific molecular alterations related to DNA repair and replication stress, suggesting potential biomarkers for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of the WEE1 inhibitor adavosertib (AZD1775) in combination with carboplatin in children with advanced malignancies: Arm C of the AcSé-ESMART trial. Gatz, SA., Harttrampf, AC., Brard, C., et al.[2023]

In a phase II trial involving 150 patients with metastatic castration-resistant prostate cancer (mCRPC), the addition of capivasertib to standard chemotherapy did not significantly prolong composite progression-free survival (cPFS) compared to placebo, with median cPFS of 7.03 months for capivasertib versus 6.70 months for placebo.

However, capivasertib was associated with a significant improvement in overall survival (OS), with a median OS of 31.15 months for the capivasertib group compared to 20.27 months for the placebo group, suggesting potential benefits that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). Crabb, SJ., Griffiths, G., Marwood, E., et al.[2022]

A high-throughput drug screen identified olaparib, a PARP inhibitor, as the most effective drug to combine with selinexor in ovarian cancer, showing significant antitumor effects in both in vitro and in vivo models.

The combination treatment resulted in lower tumor weights and fewer tumor nodules in mouse models, with mechanisms indicating reduced DNA damage repair protein expression and increased tumor suppressor protein expression, suggesting a promising strategy for enhancing the efficacy of PARP inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models. Handley, KF., Rodriguez-Aguayo, C., Ma, S., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children's Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515). [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Phase I/II study of the WEE1 inhibitor adavosertib (AZD1775) in combination with carboplatin in children with advanced malignancies: Arm C of the AcSé-ESMART trial. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

SGN-B6A: A New Vedotin Antibody-Drug Conjugate Directed to Integrin Beta-6 for Multiple Carcinoma Indications. [2023]